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Questions and Answers on Levothyroxine Sodium Products

[10/3/2007]

1. What action is FDA taking today?

FDA has decided to require each approved levothyroxine sodium product to meet a 95-105 percent potency specification throughout its shelf life, that is, to degrade by no more than 5 percent from its labeled potency amount. Currently, these products are required to meet a USP-authorized potency specification of 90-110 percent, which is typical for most drug products. The potency specification provides for limited, permissible degradation over a product’s shelf life.

2. What are levothyroxine sodium drug products and what are they used for?

Levothyroxine sodium is the sodium salt of the levo isomer of the thyroid hormone thyroxine. Thyroid hormones affect protein, lipid, and carbohydrate metabolism, growth, and development. Orally administered levothyroxine sodium is used as replacement therapy in conditions characterized by diminished or absent thyroid function, such as cretinism, myxedema, nontoxic goiter, or hypothyroidism. Levothyroxine sodium may be used to suppress the secretion of thyrotropin in the management of simple nonendemic goiter, chronic lymphocytic thyroiditis, and thyroid cancer.

3. Why is FDA taking this action?

FDA believes that narrowing the potency specifications will improve the quality of certain levothyroxine sodium products. This action will address concerns about variability in the stability profiles of FDA-approved levothyroxine sodium products and the clinical consequences of this variability in stabilizing particularly vulnerable patients, such as those with thyroid cancer. This action is consistent with FDA’s previous regulatory actions intended to ensure that levothyroxine sodium drug products maintain their quality over the course of their shelf lives.

Levothyroxine sodium drug products have been marketed for decades in the United States and are important tools for the management of thyroid balance. Over the past decade, the Agency has spent considerable resources to ensure that levothyroxine sodium products are as safe and effective as possible. In 1997, FDA addressed observed product stability and potency problems at that time by declaring orally administered levothyroxine sodium drug products to be new drugs and requiring new drug application (NDA) submissions for all marketed levothyroxine sodium products. Subsequently, we have continued to monitor the stability of these products.

4. What prompted FDA to take this action?

In response to physician and patient concerns about product performance, particularly for patients taking levothyroxine sodium products after prescription refills that may involve products from different manufacturers, FDA decided to examine the stability profile of each approved product. Two years ago, we requested product stability data from manufacturers of all the approved, marketed levothyroxine sodium drug products manufactured between July 2003 and June 2005 to obtain a stability profile for each marketed, levothyroxine sodium product. These data provided a much more complete stability profile for each product than the limited data that was available to the Agency at the time of initial product approval.

It is evident from this more recent data that there is a trend of potency loss in levothyroxine sodium products, with some formulations showing potency amounts approaching 90 percent of labeled potency by the established expiration date. Although all approved levothyroxine sodium products meet the current potency specifications, the stability data provided to the Agency revealed that the potency of several of these products declines rapidly over the labeled shelf life, representing variable stability patterns and resulting in varied shelf lives. This variability is reflected in expiration dating periods that establish shelf life that vary between these products—from a minimum of 8 months to a maximum of 24 months.

5. What is FDA’s advice to consumers? Are currently marketed levothyroxine sodium products safe?

Consumers should continue to take their thyroid hormones as directed by their doctors. We recommend that these products be stored in a dry place at room temperature—avoid humid, hot conditions, such as bathrooms. Levothyroxine sodium products are very important tools in the management of a variety of thyroid conditions. We believe that these products are safe and effective, although we continue to closely monitor them for any possible quality issues.

6. Why is there a 2-year time period for products to meet the revised specifications?

FDA has requested that manufacturers comply with the revised potency specification within 2 years. Because of medical necessity, it is important to have an adequate supply of this drug product. When FDA declared levothyroxine sodium a new drug in 1997, manufacturers were given 3 (later extended to 4) years to submit applications and obtain FDA approval of their respective products. Although the new potency specification represents product improvement, the quality and consistency of the currently approved levothyroxine sodium products reflect significant improvement compared to those that were historically available before 1997. It is important to note that some manufacturers have already demonstrated that their marketed levothyroxine sodium products can meet the revised specifications, and others have made assurances that they can meet a revised potency specification with formulation and/or manufacturing changes. The 2-year time period for products to meet the revised specifications will enable this transition without adversely affecting public health.

7. In May 2005, FDA held a public meeting in conjunction with three leading medical endocrine societies, and in October 2006, we held a joint meeting of the Endocrine and Metabolic Drugs Advisory Committee (EMDAC) and the Advisory Committee for the Pharmaceutical Sciences (ASCPS). How does this action relate to those meetings?

As we have made regulatory decisions over the past decade, some, including members of the leading medical endocrine societies, questioned our methodology for determining bioequivalence and the resulting interchangeability of levothyroxine sodium products. In May of 2005, we held a public meeting to explain our bioequivalence rationale and methodology to members of the thyroid community. During this meeting, some endocrinologists expressed concern about the performance of currently approved levothyroxine sodium products and stated that patients are being harmed by involuntary substitution of levothyroxine sodium products (see transcript of the 05/23/2005 Public Meeting, Docket No. 2005N-0137, posted 07/11/2005).

In response to these concerns, FDA requested product stability data from levothyroxine sodium drug manufacturers, which was then provided to the agency in the spring of 2006. We presented these data and analyses to the joint meeting of the EMDAC and ASCPS to discuss the potency and stability of these products (see Joint Meeting transcript, background materials, and presentations). First, the clinical experts in endocrinology on the EMDAC unanimously agreed that allowing the usual 10 percent loss during a product’s shelf life could have clinically relevant consequences. Second, the vast majority of the joint committee agreed that the potency specification for levothyroxine sodium products should be narrowed from 90-110 percent to 95-105 percent. These recommendations supported FDA’s own conclusions about potential clinical consequences from the potency specification and the need to tighten this specification. FDA believes that requiring all marketed levothyroxine sodium products to adhere to a tighter potency specification will minimize any clinical differences that may result from switching between different levothyroxine sodium products or refilling a prescription with the same prescribed product.

8. Which manufacturers of levothyroxine sodium drug products are impacted by this action?

All manufacturers of approved levothyroxine sodium oral formulations (tablet or capsule) are impacted by this action. They are:

Abbott (Synthroid)

Alara (Levo-T)

Jerome Stevens (Unithroid)

Jones Pharma/King (Levoxyl)

Lloyd (distributed by Forest) (Levothroid)

Genpharm

Mylan

Institute Biochimique (Tirosint)

Vintage (Levolet, not marketed in the U.S)

9. What does this mean for the approved products?

Some products may meet the new potency specification throughout their current shelf life and require no change. The expiration dating period of some strengths and/or package presentations for some products may need to be shortened. For other products, manufacturers may need to alter manufacturing processes or product formulation to improve their stability.